SK11582001A3 - N-[2-hydroxy-3-(1-piperidinyl)propoxy]pyridine-1-oxide-3- carboximidoyl chloride and its use in the treatment of insulin resistance - Google Patents
N-[2-hydroxy-3-(1-piperidinyl)propoxy]pyridine-1-oxide-3- carboximidoyl chloride and its use in the treatment of insulin resistance Download PDFInfo
- Publication number
- SK11582001A3 SK11582001A3 SK1158-2001A SK11582001A SK11582001A3 SK 11582001 A3 SK11582001 A3 SK 11582001A3 SK 11582001 A SK11582001 A SK 11582001A SK 11582001 A3 SK11582001 A3 SK 11582001A3
- Authority
- SK
- Slovakia
- Prior art keywords
- pyridine
- hydroxy
- oxide
- piperidinyl
- propoxy
- Prior art date
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- 206010022489 Insulin Resistance Diseases 0.000 title claims abstract description 35
- 208000001072 type 2 diabetes mellitus Diseases 0.000 title claims abstract description 35
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- C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
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- A—HUMAN NECESSITIES
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- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
Abstract
Description
Oblasť technikyTechnical field
Tento vynález sa týka halidového derivátu 0—(3piperidino-2-hydroxy-l-propyl) kyseliny hydroxymovej, jeho farmaceutického použitia a farmaceutických výrobkov obsahujúcich tento derivát ako aktívnu zložku. Menovite sa vynález týka chloridu N- [2-hydroxy-3-(1-piperid.inyl) propoxy]pyridínl-oxid-3-karboximidoylu, jeho stereoizomérov, rovnako ako aj ich kyslých adičných solí. Ďalej sa vynález týka použitia týchto zlúčenín pre liečenie inzulínovej rezistencie a farmaceutických výrobkov obsahujúcich tieto deriváty ako aktívnu zložku.The present invention relates to a halide derivative of O- (3-piperidino-2-hydroxy-1-propyl) hydroxymic acid, its pharmaceutical use and pharmaceutical products containing the derivative as an active ingredient. More particularly, the invention relates to N- [2-hydroxy-3- (1-piperidinyl) propoxy] pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers, as well as their acid addition salts. Furthermore, the invention relates to the use of these compounds for the treatment of insulin resistance and pharmaceutical products containing these derivatives as an active ingredient.
Doterajší stav technikyBACKGROUND OF THE INVENTION
Halidové deriváty 0-(3-piperidino-2-hydroxy-l-propyl) hydroxymovej kyseliny sú dobre známe z Európskej patentovej špecifikácie č. 0 417 210 BI. Podlá tejto patentovej špecifikácie vykazujú tieto zlúčeniny selektívny beta blokátorový účinok a sú tak vhodné pre liečenie diabetickej angiopatie, predovšetkým diabetickej retinopatie a nefropatie.The halide derivatives of O- (3-piperidino-2-hydroxy-1-propyl) -hydroxy acid are well known from European Patent Specification No. 5,940,049. 0 417 210 BI. According to this patent specification, these compounds show a selective beta blocker effect and are thus suitable for the treatment of diabetic angiopathy, in particular diabetic retinopathy and nephropathy.
Podlá PCT publikácie WO 98/06400, halidové deriváty 0(3-piperidino-2-hydroxy-l-propyl)hydroxymovej kyseliny a iné zlúčeniny podobnej štruktúry sú účinné pre ochranu a regeneráciu cievnych endoteliálnych buniek, a sú aktívnymi látkami pre liečenie ochorení spôsobených dysfunkciou endotelu.According to PCT publication WO 98/06400, halide derivatives of O (3-piperidino-2-hydroxy-1-propyl) hydroxymic acid and other compounds of similar structure are effective for the protection and regeneration of vascular endothelial cells, and are active agents for the treatment of diseases caused by dysfunction endothelium.
WO 97/16439 popisuje stimulačný účinok chaperónovej expresie mnohých derivátov hydroxylamínu, medzi nimi halidy O-(3-piperidino-2-hydroxy-l-propyl) hydroxymovej kyseliny. Dobre je známe použitie týchto zlúčenín pre liečenie ochorení spojených s funkciou chaperónového systému. V tejto patentovej žiadosti sú definované a nárokované, medzi inými, Noxid deriváty 0-(3-piperidino-2-hydroxy-l-propyl)-3-pyridyl hydroxymovej kyseliny (okrem iných) ako nové zlúčeniny, avšak príprava je popísaná len pre piperidin-N-oxid a pre zlúčeniny obsahujúce N-oxidové skupiny v piperidínovom alebo pyridínovom kruhu. Zlúčenina predkladaného vynálezu nie je uvedená vo vyššie spomínanej patentovej žiadosti.WO 97/16439 discloses the stimulatory effect of chaperone expression of many hydroxylamine derivatives, including O- (3-piperidino-2-hydroxy-1-propyl) hydroxymic acid halides. It is well known to use these compounds for the treatment of diseases associated with the function of the chaperone system. This patent application defines and claims, among others, O- (3-piperidino-2-hydroxy-1-propyl) -3-pyridyl hydroxymic acid derivatives (among others) as novel compounds, but the preparation is described only for piperidine -N-oxide and for compounds containing N-oxide groups in the piperidine or pyridine ring. The compound of the present invention is not disclosed in the aforementioned patent application.
Inzulínová rezistencia je patologický stav, pri ktorom je znížený účinok inzulínu. Všeobecne tento stav je spojený s diabetom, hoci môže existovať nezávisle na diabete. V dôsledku inzulínovej rezistencie telo potrebuje vyššie a vyššie koncentrácie inzulínu pre kontrolu metabolizmu cukrov, lipidov a proteínov, čo vedie k extrémne vysokým koncentráciám inzulínu. Bolo dokázané, že dlhotrvajúce vysoké koncentrácie inzulínu sú nezávislým rizikovým faktorom pre srdcovo-mozgocievnych ochorení.Insulin resistance is a pathological condition in which the effect of insulin is reduced. Generally, this condition is associated with diabetes, although it may exist independently of diabetes. Due to insulin resistance, the body needs higher and higher insulin concentrations to control the metabolism of sugars, lipids and proteins, resulting in extremely high insulin concentrations. Prolonged high insulin concentrations have been shown to be an independent risk factor for cardiovascular disease.
Zníženie inzulínovej rezistencie je dôležité pri oboch typoch diabetu: v prípade diabetu typu 2, je prítomný ako hlavný etiologický faktor, kým v prípade diabetu 1, inzulínová rezistencia je spôsobená toxicitou glukózy rovnako ako nadmerným množstvom exogénne podávaného inzulínu pre terapeutické účely.Reduction of insulin resistance is important in both types of diabetes: in type 2 diabetes, it is present as a major etiological factor, whereas in diabetes 1, insulin resistance is due to glucose toxicity as well as excessive amounts of exogenously administered insulin for therapeutic purposes.
Pre redukovanie inzulínovej rezistencie sa používa mnoho aktívnych látok. Medzi nimi sú najvýznamnejšie výrobky, ktoré zvyšujú citlivosť voči inzulínu. Najznámejšou takouto látkou je troglitazon, patriaci do tiazolidin-dion skupiny (A. R. Saltiel a spol., Diabetes 45/12/1996 str. 1661-1669, a S. Kumar a spol., Diabetológia 1996/39/6 str. 701-709). Hlavným účinkom tejto zlúčeniny je zníženie inzulínovej rezistencie spôsobené poklesom periférnych koncentrácií inzulínu za bazálneho stavu a aj po stimulácii glukózou. Výsledkom je zlep·· ·· ·· ·· ·· ···· ···· ··· • · · · · · ··· · · · · ····· ···· ···· ·· ·· ·· ·· ··· šenie metabolizmu cukrov a rovnako tiež zlepšenie mnohých patologických odchyliek spôsobených sekundárnym účinkom vysokých hladín inzulínu, akými sú hyperlipidémia a patologická hemostáza. Jeho jednoznačný pozitívny účinok je v znížení kardiovaskulárneho rizika. Nevýhodou je však to, že môže spôsobiť vážne vedľajšie účinky, hlavne poškodenie pečene, a preto je jeho používanie obmedzené a vyžaduje si veľkú pozornosť.Many active ingredients are used to reduce insulin resistance. Among them are the most prominent products that increase insulin sensitivity. The best known such is troglitazone, belonging to the thiazolidinedione group (AR Saltiel et al., Diabetes 45/12/1996 pp. 1661-1669, and S. Kumar et al., Diabetology 1996/39/6 pp. 701-709 ). The main effect of this compound is a decrease in insulin resistance caused by a decrease in peripheral insulin concentrations in the basal state and also after glucose stimulation. The result is an improvement in the environment. · Increase in sugar metabolism as well as amelioration of many pathological abnormalities due to secondary effects of high insulin levels such as hyperlipidemia and pathological haemostasis. Its clear positive effect is in reducing cardiovascular risk. The disadvantage, however, is that it can cause serious side effects, especially liver damage, and therefore its use is limited and requires great attention.
Podstata vynálezuSUMMARY OF THE INVENTION
Štúdie s halidovými derivátmi 0-(3-piperidino-2-hydroxy1-propyl) hydroxymovej kyseliny, podrobné skúšky chloridu maleinanu 0-(3-piperidino-2-hydroxy-l-propyl)-3-pyridín hydroxymovej kyseliny, známy ako Bimoclomol, ukázali, že jeho najvýznamnejší účinok je v pôsobení na patologické následky chronickej neuropatie: významne zlepšuje motorickú a senzorickú vodivosť nervových dráh, ktoré sú znížené pri diabete; má priaznivé účinky na patologické odchýlky autonómnej neuropatie. Ďalej, v pokusoch na zvieratách a u ľudí v II fáze skúšok, sa ukázalo, že znižuje patologické diabetické vylučovanie albumínu močom a v skúškach u zvierat sa ukázalo, že znižuje patologické histologické a elektrofyziologické zmeny spôsobené diabetickou retinopatiou. Avšak Bimoclomol nebol nenížil inzulínovú rezistenciu.Studies with O- (3-piperidino-2-hydroxy-1-propyl) -hydroxy acid halide derivatives, detailed tests of O- (3-piperidino-2-hydroxy-1-propyl) -3-pyridine-hydroxymic acid maleic chloride, known as Bimoclomol, have shown that its most important effect is in the treatment of the pathological consequences of chronic neuropathy: it significantly improves the motor and sensory conductivity of nerve pathways that are reduced in diabetes; has beneficial effects on pathological abnormalities of autonomic neuropathy. Furthermore, in animal and human trials in phase II trials, it has been shown to reduce the pathological diabetic excretion of albumin in urine and in animal trials has been shown to reduce the pathological histological and electrophysiological changes caused by diabetic retinopathy. However, Bimoclomol was not insulin resistant.
V súčasnosti neexistujú žiadne prípravky, ktoré by znižovali inzulínovú rezistenciu a súčasne účinne liečili odchýlky spôsobené tromi komplikáciami chronického diabetu.There are currently no agents that reduce insulin resistance while effectively treating aberrations caused by the three complications of chronic diabetes.
Pri výskume týkajúcom sa vhodných aktívnych látok, bola testovaná biologická aktivita N-oxid derivátov Bimiclomolu. V predbežnej skúške boli sledované účinky troch N-oxid derivátov Bimoclomolu na motorickú a senzorickú neuropatiu u STZ diabetických Wistar potkanov. Spôsobom, ktorý bude podrobne ·· ·· ·· ·· ·· ···· · e · · ·· ··· · · · · ·· • · · · · · ··· · · · ····· ··· ···· ·· ·· ·· ·· • ο ·· · popísaný v Pokuse 2, sa zistila účinnosť troch N-oxid derivátov Bimoclomolu v zmysle zlepšenia zníženej rýchlosti periférnej motorickej a senzorickej vodivosti nervov u STZ diabetu. Výsledky sú uvedené v nasledujúcej tabuľke.In a study of suitable active substances, the biological activity of the N-oxide derivatives of Bimiclomol was tested. In a preliminary test, the effects of three N-oxide derivatives of Bimoclomol on motor and sensory neuropathy in STZ diabetic Wistar rats were studied. In a way that will be detailed in detail, and in detail. As described in Experiment 2, the efficacy of the three N-oxide derivatives of Bimoclomol was found to improve the reduced rate of peripheral motor and sensory conduction of nerves in STZ diabetes. The results are shown in the following table.
*p < 0,05 oproti Bimoclomolu **p < 0,01 oproti Bimoclomolu* p <0.05 vs. Bimoclomol ** p <0.01 vs. Bimoclomol
Z vyššie uvedených výsledkov sa zdá, že pyridín N-oxid derivát Bimoclomolu je rovnocenný Bimoclomolu, kým dva ďalšie deriváty N-oxidu majú významne slabší účinok na motorickú a senzorickú neuropatiu. Na základe skúsenosti sa pokračovalo v pokusoch s derivátom pyridín N-oxidu Bimoclomolu, menovite chloridom N-[2-hydroxy-3-(1-piperidinyl)-1-propoxy]-pyridínl-oxid-3-karboximydoyu.From the above results, the pyridine N-oxide derivative of Bimoclomol appears to be equivalent to Bimoclomol, while the two other N-oxide derivatives have a significantly weaker effect on motor and sensory neuropathy. Experience has continued in experiments with the pyridine N-oxide derivative of Bimoclomol, namely N- [2-hydroxy-3- (1-piperidinyl) -1-propoxy] -pyridine-oxide-3-carboximydoyl chloride.
Náš výskum poskytol neočakávaný výsledok. Zistilo sa, že chlorid N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridín-1oxid-3-karboximidoylu znižuje periférnu inzulínovú rezistenciu a okrem toho vykazuje účinok rovnajúci sa, alebo v niek5 ·· torých prípadoch väčší ako Bimoclomol, pri liečení vyššie uvedených troch hlavných diabetických komplikácií. Pre tieto vlastnosti je zlúčenina vhodná pre liečenie chronických diabetických komplikácií, predovšetkým retinopatie, neuropatie a nefropatie, súčasne vykazuje zníženie periférnej inzulínovej rezistencie. Je však tiež vhodný pre liečenie nediabetickej patologickej inzulínovej rezistencie a na ňu sa vzťahujúcich akýchkoľvek patologických stavov.Our research has produced an unexpected result. It has been found that N- [2-hydroxy-3- (1-piperidinyl) -propoxy] -pyridine-1-oxide-3-carboximidoyl chloride reduces peripheral insulin resistance and, in addition, exhibits an effect equal to or greater in some cases as Bimoclomol, in the treatment of the above three major diabetic complications. Because of these properties, the compound is suitable for the treatment of chronic diabetic complications, in particular retinopathy, neuropathy and nephropathy, while exhibiting a decrease in peripheral insulin resistance. However, it is also suitable for the treatment of non-diabetic pathological insulin resistance and any pathological conditions related thereto.
Výhodné biologické vlastnosti chloridu N-[2-hydroxy-3(1-piperidinyl)-propoxy]-pyridín-l-oxid-3-karboximidoylu boli dokázané nasledujúcimi pokusmi. V týchto skúškach boli použité zlúčeniny maleinanu N-[2-hydroxy-3-(1-piperidinyl)-propoxy] -pyridín-l-oxid-3-karboximidoyl chloridu alebo maleinanu vhodnej opticky aktívnej zlúčeniny. V popise pokusov je maleinan racemickej zlúčeniny označený ako Zlúčenina A, kým maleinan opticky aktívneho stereoizoméru je vždy špecificky označený.The advantageous biological properties of N- [2-hydroxy-3- (1-piperidinyl) -propoxy] -pyridine-1-oxide-3-carboximidoyl chloride have been demonstrated by the following experiments. In these assays, N- [2-hydroxy-3- (1-piperidinyl) -propoxy] -pyridine-1-oxide-3-carboximidoyl chloride or maleate compounds of a suitable optically active compound were used. In the description of the experiments, the maleate of the racemic compound is designated Compound A, while the maleate of the optically active stereoisomer is always specifically labeled.
Pokus 1Experiment 1
Účinok podávania zlúčeniny A a Bimoclomolu na metabolizmus cukrov u obéznych, inzulínorezistentných Zucker fa/fa potkanov s poškodenou glukózovou toleranciou, 2-mesačné podávanieEffect of administration of Compound A and Bimoclomol on carbohydrate metabolism in obese, insulin-resistant Zucker fa / fa rats with impaired glucose tolerance, 2 months administration
Materiál a metódy:Material and methods:
V pokusoch boli použité Zucker fa/fa potkany (Charles River Laboratories Inc.). U monozygotných zvierat je prítomná obezita, inzulínová rezistencia, vysoká hladina inzulínu, glukózová intolerancia a hypertriglyceridémia výsledkom mutácie hypotalamického receptora pre leptín. V dôsledku uvedených vlastností, sú takéto zvieratá považované za prijateľný model skorého diabetu 2. typu.Zucker fa / fa rats (Charles River Laboratories Inc.) were used in the experiments. In monozygous animals, obesity, insulin resistance, high insulin levels, glucose intolerance and hypertriglyceridemia are present as a result of mutation of the hypothalamic leptin receptor. Due to the above properties, such animals are considered to be an acceptable model of early type 2 diabetes.
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Na začiatku pokusu boli zvieratá individuálne umiestnené do metabolických klietok na 24 hodín a po jednom alebo dvoch mesiacoch liečenia opäť na 24 hodín. V metabolických klietkach sa zbieral moč.At the start of the experiment, the animals were individually housed in metabolic cages for 24 hours and after one or two months of treatment again for 24 hours. Urine was collected in metabolic cages.
Zvieratá dostávali buď testovanú látku alebo fyziologický roztok sondou jedenkrát denne v týždňoch 14 až 22.Animals received either the test substance or saline by gavage once daily at weeks 14-22.
Biochemické parametre krvi a moča boli hodnotené Kodak Ectachem 700 automatickým analyzátorom. Celkový obsah proteínov v moči bol stanovený spektrofotometricky pomocou Bradfordového farbenia (Hitachi U-3200) pri vlnovej dĺžke 595 nm. Koncentrácia inzulínu v sére bola stanovená pomocou RIA metódy, za použitia anti-potkaních protilátok.Biochemical parameters of blood and urine were evaluated by Kodak Ectachem 700 automatic analyzer. Total protein content in urine was determined spectrophotometrically by Bradford staining (Hitachi U-3200) at 595 nm. Serum insulin concentration was determined by the RIA method, using anti-rat antibodies.
Systolický, diastolický tlak krvi a srdcová rýchlosť boli merané týždenne na chvoste potkanov (takzvanou „tail cuff method) použitím Leica 200 automatickým analyzátorom. Po dvoch mesiacoch podávania bola meraná glukózová tolerancia intraperitoneálnym glukózovým tolerančným testom (2 g/kg ip.) Výsledky:Systolic, diastolic blood pressure and heart rate were measured weekly on the tail of the rat (the so-called tail cuff method) using a Leica 200 automatic analyzer. After two months of administration, glucose tolerance was measured by the intraperitoneal glucose tolerance test (2 g / kg ip.) Results:
Bimoclomol podávaný denne v dávke 20 mg/kg per os významne znížil hladinu glukózy na lacno, avšak neovplyvnil koncentráciu inzulínu na lacno.Bimoclomol administered daily at 20 mg / kg orally significantly reduced glucose levels cheaply but did not affect insulin concentration cheaply.
V porovnaní s predchádzajúcimi hodnotami, sa neočakávane zistilo, že Zlúčenina A podávaná denne v dávke 20 mg/kg per os, významne znížila tak hladiny glukózy ako aj inzulínu na lačno, pokles inzulínu bol približne 50 %. Výsledky sú uvedené v Tabuľke 1 a na Obrázku 1.Compared to previous values, it was unexpectedly found that Compound A, administered daily at 20 mg / kg orally, significantly reduced both fasting glucose and fasting insulin levels, with an insulin decrease of approximately 50%. The results are shown in Table 1 and Figure 1.
Tabuľka 1Table 1
Účinok Zlúčeniny A a Bimoclomolu na koncentrácie krvnej glukózy a inzulínu na lacno.Effect of Compound A and Bimoclomol on cheap blood glucose and insulin concentrations.
**p < 0,001, ***p < 0,0001, porovnanie voči obéznym kontrolám** p <0.001, *** p <0.0001, comparison to obese controls
V priebehu intraperitoneálneho glukózového tolerančného testu, ani Bimoclomol a ani Zlúčenina A neovlyvnili plochu pod glukózovou krivkou (AUC). Avšak v prípade AUC pre inzulín, bol prítomný rozdiel medzi dvoma zlúčeninami: Bimoclomol nemal žiaden účinok, kým Zlúčenina A znížila plochu pod krivkou významne, na rovnakú úroveň aká bola zaznamenaná pre štíhle kontrolné zvieratá. Výsledky sú uvedené v Tabuľke 2 a na Obrázku 2.During the intraperitoneal glucose tolerance test, neither Bimoclomol nor Compound A affected the area under the glucose curve (AUC). However, in the case of insulin AUC, there was a difference between the two compounds: Bimoclomol had no effect until Compound A reduced the area under the curve significantly, to the same level as observed for lean control animals. The results are shown in Table 2 and Figure 2.
Tabuľka obsahuje hodnoty plochy pod krivkou (AUC) medzi 0 až 60 minútou.The table shows the AUC values between 0 and 60 minutes.
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Tabuľka 2Table 2
Účinok 2-mesačného podávania Bimoclomolu a Zlúčeniny A na glukózovú toleranciu u obéznych, inzulinorezistentných, hyperinzulinemických Zucker fa/fa potkanov s poškodenou glukózovou toleranciouEffect of 2-month administration of Bimoclomol and Compound A on glucose tolerance in obese, insulin-resistant, hyperinsulinemic Zucker fa / fa rats with impaired glucose tolerance
***p < 0,0001, porovnanie voči obéznym kontrolám*** p <0.0001, comparison to obese controls
Záver:conclusion:
Zlúčenina A významne znižuje periférnu inzulínovú rezistenciu, zatiaľ čo Bimoclomol nemá takýto účinok.Compound A significantly reduces peripheral insulin resistance, while Bimoclomol has no such effect.
Pokus 2Experiment 2
Účinok 1-mesačného podávania Zlúčeniny A a Bimoclomolu na patologické odchýlky vyvolané periférnou neuropatiu u STZdiabetických Wistar potkanovEffect of 1-month administration of Compound A and Bimoclomol on peripheral neuropathy-induced pathological abnormalities in STZdiabetic Wistar rats
Materiál a metódy:Material and methods:
V pokusoch boli použité potkany, samci kmeňa Wistar (Charles River Laboratories, Inc). Na začiatku pokusu mali zvieratá hmotnosť 340 až 370 g. Diabetes bol navodený intravenóznym podaním jednej dávky streptozotocínu (STZ, Sigma, St. Louis, MO) v množstve 45 mg/kg, rozpusteného vo fyziolo9Male Wistar rats (Charles River Laboratories, Inc) were used in the experiments. At the start of the experiment, the animals weighed 340-370 g. Diabetes was induced by intravenous administration of a single dose of streptozotocin (STZ, Sigma, St. Louis, MO) in an amount of 45 mg / kg dissolved in physiology.
• e • · · · · • · · · · • ··· · * · • · · · ·· ·· ·· gíckom roztoku. Prítomnosť diabetu bola overená nasledujúci deň stanovením glukózy v krvi, akceptovala sa hodnota vyššia ako 15 mmol/1.• e • • • • • • • • • • • • • • • • • • • • • • • • • • - The presence of diabetes was verified the next day by blood glucose determination, a value greater than 15 mmol / l was accepted.
Skúška a testované látky boli podávané zvieratám per os, jedenkrát denne.The test and test substances were administered orally to animals once a day.
Pri hodnotení rýchlosti vodivosti nervov (NCV), bola použitá metóda podlá Stanleyho, modifikovaná De Konigom a Gispenom. Zvieratá boli anestezované súčasným podaním Hyponormu (1 mg/kg ip., Janssen, Tilburg, Dánsko), fluanisonu (10 mg/ml) a fenyl citrátu (0,2 mg/ml) . Potom boli v štandardných bodoch stimulované lavý ischiadický a lavý tibiálny nerv. Supramaximálna stimulácia (štvorcový impulz, 0,03 ms) bola vyvolaná platinovou ihlovou elektródou pomocou NihonKohden (model SEN-1104, Japonsko) stimulátora. Elektromyogram (EMG) z jedného svalu a zosilnený myografom (Elma-Schonander, Štokholm, Švédsko) bol potom analyzovaný programom Metlab pre Windows (Mathwork Inc., UK). Rozsah NCV poškodenia spôsobeného diabetom bol vyjadrený v m/s. Účinnosť liečenia bola porovnaná v tomto vyjadrení percentuálne (%). Pre štatistické hodnotenie bol použitý nepárový T-test, alebo jednocestná ANOVA (spolu s Newman-Keuls post hoc testom), (Graphpad Instat, San Diago, CA).In evaluating nerve conduction velocity (NCV), the Stanley method modified by De Konig and Gispen was used. The animals were anesthetized by co-administration of Hyponorm (1 mg / kg ip, Janssen, Tilburg, Denmark), fluanisone (10 mg / ml) and phenyl citrate (0.2 mg / ml). Then, the left sciatica and left tibial nerve were stimulated at standard points. Supramaximal stimulation (square pulse, 0.03 ms) was induced with a platinum needle electrode using a NihonKohden (model SEN-1104, Japan) stimulator. A single muscle electromyogram (EMG) and amplified by myograph (Elma-Schonander, Stockholm, Sweden) was then analyzed by Metlab for Windows (Mathwork Inc., UK). The extent of NCV damage caused by diabetes was expressed in m / s. The treatment efficacy was compared in this expression as a percentage (%). An unpaired T-test, or a one-way ANOVA (together with the Newman-Keuls post hoc test), (Graphpad Instat, San Diago, CA) was used for statistical evaluation.
Výsledky:The results:
Bimoclomol podávaný denne v jednej dávke 20 mg/kg a Zlúčenina A podávaná denne v jednej dávke 5 mg/kg významne zlepšili rýchlosť motorickej (MNCV) a senzorickej (SNCV) vodivosti nervov u diabetických zvierat. Použitie vyššej dávky ako 10 mg/kg Zlúčeniny A nespôsobilo zvýšenie účinku. Výsledky sú uvedené v Tabuľke 3.Bimoclomol given daily as a single dose of 20 mg / kg and Compound A given daily as a single dose of 5 mg / kg significantly improved the rate of motor (MNCV) and sensory (SNCV) nerve conduction in diabetic animals. Use of a dose greater than 10 mg / kg of Compound A did not cause an increase in efficacy. The results are shown in Table 3.
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Tabulka 3Table 3
Účinok podávania Zlúčeniny A a Bimoclomolu na rýchlosť zníženej vodivosti nervov (NCV) u STZ-diabetických (STZ-DB) Wistar potkanovEffect of Compound A and Bimoclomol administration on the rate of reduced nerve conduction (NCV) in STZ-diabetic (STZ-DB) Wistar rats
***p < 0,001*** p <0.001
Pokus 3Experiment 3
Účinok 1-mesačného podávania Zlúčeniny A a Bimoclomolu na patologické odchýlky pri diabetickej autonómnej neuropatii u STZ-diabetických Wistar potkanochEffect of 1-month administration of Compound A and Bimoclomol on pathological abnormalities in diabetic autonomic neuropathy in STZ-diabetic Wistar rats
Materiál a metódy:Material and methods:
V pokusoch boli použité potkany kmeňa Wistar (Charles River Laboratories Inc.), samci s počiatočnou hmotnosťou 340 až 370 g. Diabetes bol vyvolaný intravenóznym podaním jednej dávky streptozotocínu v dávke 45 mg/kg (STZ, Sigma, St. Louis, MO) rozpustenom vo fyziologickom roztoku. Prítomnosť diabetu bola skontrolovaná nasledujúci deň po podaní hodnotením glukózy v krvi, akceptovali sa hodnoty vyššie ako 15 mmol/1.Wistar rats (Charles River Laboratories Inc.), males weighing 340-370 g, were used in the experiments. Diabetes was induced by intravenous administration of a single dose of streptozotocin at a dose of 45 mg / kg (STZ, Sigma, St. Louis, MO) dissolved in saline. The presence of diabetes was checked the next day after administration of blood glucose, values above 15 mmol / l were accepted.
Testované a porovnávacie látky boli podávané potkanom denne per os.Test and comparator compounds were administered to rats daily orally.
Pokusy boli uskutočnené v celkovej anestéze potkanov navodenej intraperitoneálnym podaním 60 mg/kg pentobarbitálu sodného (Nembutal, Sanofi, Phylaxia). Intratracheálna hadička alebo polyetylénová kanyla bola vsunutá do femorálnej artérie a vény. Arteriálny katéter bol napojený na simultánny merač systolického a diastolického krvného tlaku (online automatické meranie hodnotené Haemosys počítačovým programom). Po 20 minútovej vyrovnávacej perióde boli intravenózne podané nasledujúce látky: noradrenalin, 5 pg/kg, i.v.; izoproterenol 0,4 pg/kg, i.v.; stimulácia n. vagus (2 V, trvanie: 500 psek, posun: 1 msek). Účinky látok boli zaznamenávané počas 10 minút.The experiments were performed under general anesthesia of rats induced by intraperitoneal administration of 60 mg / kg sodium pentobarbital (Nembutal, Sanofi, Phylaxia). The intratracheal tube or polyethylene cannula was inserted into the femoral artery and vein. The arterial catheter was connected to a simultaneous systolic and diastolic blood pressure meter (online automatic measurement evaluated by the Haemosys computer program). Following the 20 minute equilibration period, the following agents were administered intravenously: noradrenaline, 5 µg / kg, i.v .; isoproterenol 0.4 pg / kg, i.v .; stimulation n. vagus (2 V, duration: 500 psek, shift: 1 msec). The effects of the substances were recorded for 10 minutes.
Výsledky:The results:
Autonómna neuropatia je jednou z hlavných pričiň spôsobujúcich náhle srdcové úmrtie u diabetikov a iných ochorení (napríklad ochorení pečene). Preto sú veľmi dôležité všetky látky, ktoré môžu účinne znižovať patologické odchýlky autonómnej neuropatie.Autonomic neuropathy is one of the major causes of sudden cardiac death in diabetics and other diseases (such as liver diseases). Therefore, all substances that can effectively reduce the pathological aberrations of autonomic neuropathy are very important.
V pokusoch denná jedna dávka 20 mg/kg Bimoclomolu alebo Zlúčeniny A významne znižovala ťažké patologické odchýlky autonómneho neuropatologického pôvodu.In the experiments, a single daily dose of 20 mg / kg of Bimoclomol or Compound A significantly reduced severe pathological aberrations of autonomous neuropathological origin.
Tabuľka 4 zaznamenáva výsledky a porovnania.Table 4 shows the results and comparisons.
Dve šipky v Tabuľke znamenajú, že testovaná látka je štatisticky viac účinná ako iná látka.The two arrows in the Table indicate that the test substance is statistically more effective than the other substance.
·· ·· ·· ·· ·· · • ·· · · ·· · · · · · ·* · · · · · ··· · · · · ····· · · · · ···· ·· ·· ·· ·· ····························································· ·· ·· ·· ·· ···
Tabulka 4Table 4
NA: noradrenalín Ť: úpravaNA: noradrenaline J: treatment
IS: izoproterenol neúčinnéIS: isoproterenol ineffective
Pokus 4Experiment 4
Účinok 1-mesačného podávania zlúčeniny A a Bimoclomolu na patologické histologické zmeny vyvolané diabetickou retinopatiou u STZ-diabetických Wistar potkanovEffect of 1-month administration of Compound A and Bimoclomol on pathological histological changes induced by diabetic retinopathy in STZ-diabetic Wistar rats
Materiál a metódy:Material and methods:
V pokusoch boli použité potkany kmeňa Wistar, (CharlesWistar rats (Charles et al.) Were used in the experiments
River Laboratories Inc.), samci s počiatočnou hmotnosťou 340 až 370 g. Diabetes bol vyvolaný intravenóznym podaním jednej dávky streptozotocinu (STZ, Sigma, St. Louis, MO) v dávke 45 mg/kg, ktorý bol rozpustený vo fyziologickom roztoku. Prítomnosť diabetu bola overená nasledujúci deň stanovením glukózy v krvi, akceptované boli hodnoty vyššie ako 15 mmol/1.River Laboratories Inc.), males with an initial weight of 340 to 370 g. Diabetes was induced by intravenous administration of a single dose of streptozotocin (STZ, Sigma, St. Louis, MO) at a dose of 45 mg / kg, which was dissolved in saline. The presence of diabetes was verified the next day by blood glucose determination, values above 15 mmol / l were accepted.
Skúšané a kontrolné látky boli podávané zvieratám per os jedenkrát denne.Test and control substances were administered to animals orally once daily.
Po anenstéze (Calypsovet, 125 mg/kg, intraperitoneálne, Richter Rt., Maďarsko), boli oči vylúpnuté a fixované v 4 % formaldehyde rozpustenom vo fosfátovom pufri (pH: 7,4).After anesthesia (Calypsovet, 125 mg / kg, intraperitoneally, Richter Rt., Hungary), the eyes were peeled and fixed in 4% formaldehyde dissolved in phosphate buffer (pH: 7.4).
Potom boli oči ponorené do parafínu (Medim DDM P800, Lignifer L-120-92-014, farbivo: Shandon Eliott, Microtome: Leica SM 2000 R, mikroskop: Jenaval Karí Zeiss, Jena, Nemecko). Pripravilo sa niekoľko rezov očí v hrúbke 6 mikrónov a ako farbivá sa použili hematoxilyn/eozin (Fluka) a PAS (kyslý Shiff, Fluka). Rezy sa hodnotili pod svetelným mikroskopom pri zväčšení 40x a lOOx. Z reprezentačných vzoriek boli urobené fotografie a diapozitívy.Then the eyes were immersed in paraffin (Medim DDM P800, Lignifer L-120-92-014, dye: Shandon Eliott, Microtome: Leica SM 2000 R, microscope: Jenaval Kari Zeiss, Jena, Germany). Several eye sections of 6 microns were prepared and hematoxilyn / eosin (Fluka) and PAS (acidic Shiff, Fluka) were used as dyes. Sections were scored under a light microscope at a magnification of 40x and 100x. Photographs and slides were made of representative samples.
Histologické hodnotenie sa uskutočnilo u označených vzoriek, označenie skupiny bolo neznáme pre histológa. Patologické odchýlky v retine boli označené stupnicou 0 až 20, kým zmeny na šošovke boli hodnotené stupnicou v rozsahu 0 až 3.Histological evaluation was performed on the labeled samples, the group designation was unknown to the histologist. Pathological abnormalities in the retina were scored 0 to 20, while changes in the lens were scored in the range of 0 to 3.
Pre štatistické hodnotenie bol použitý Statistica 4,5 (SatSoft, USA) program. Hodnota pre negatívne prípady bola 0,1. Bol vyhotovený Box a Whisker graf.Statistica 4.5 (SatSoft, USA) program was used for statistical evaluation. The value for negative cases was 0.1. A Box and Whisker chart was made.
Pre každú skupinu v pokuse boli vypočítané priemerné hodnoty ± SE (štandardná chyba priemeru), a porovnanie medzi skupinami bolo uskutočnené pomocou neparametrického MannWhitney U-testu (Graphpad Instat, San Diego, CA).Mean values ± SE (standard mean error) were calculated for each group in the experiment, and comparisons between groups were performed using a non-parametric MannWhitney U-test (Graphpad Instat, San Diego, CA).
Výsledky:The results:
Denné podávanie jednej dávky 5 mg/kg Zlúčeniny A a denné podávanie jednej dávky 20 mg/kg Bimoclomolu významne zlepšilo po 1 mesiaci diabetickú retinopatiu vyvolanú patologickými histologickými zmenami. Z týchto dvoch zlúčenín bola Zlúčenina A štatisticky viac účinná v porovnaní s diabetickými, neliečenými zvieratami. Výsledky sú uvedené v Tabuľke 5.Daily administration of a single dose of 5 mg / kg of Compound A and daily administration of a single dose of 20 mg / kg of Bimoclomol significantly improved diabetic retinopathy induced by pathological histological changes after 1 month. Of these two compounds, Compound A was statistically more potent compared to diabetic, untreated animals. The results are shown in Table 5.
Tabuľka 5Table 5
Účinok podávania Zlúčeniny A a Bimoclomolu na patologické histologické zmeny spôsobené STZ diabetickou retinopatiouEffect of Compound A and Bimoclomol administration on pathological histological changes due to STZ diabetic retinopathy
*p < 0,05, **p < 0.01, porovnanie voči diabetickým, neliečeným zvieratám.* p <0.05, ** p <0.01, comparison to diabetic, untreated animals.
Pokus 5Experiment 5
Účinok 1-mesačného podávania Zlúčeniny A a Bimoclomolu na patologickú stratu bielkovín močom spôsobenú diabetickou nefropatiou u STZ diabetických Wistar potkanovEffect of 1-month administration of Compound A and Bimoclomol on pathological urinary protein loss due to diabetic nephropathy in STZ diabetic Wistar rats
Materiál a metódy:Material and methods:
V pokusoch boli použité potkany kmeňa Wistar, (Charles ·· ·· ·· • · · · • ·· • · · • · · ···· ·· ···· • · ·· • · ·· • ·· ··· • ·· ···· ·· •· •· • ·· •· ···Wistar rats (Charles) were used in the experiments (Charles). ··· · ···························
River Laboratories Inc.), samci s počiatočnou hmotnosťou 340 až 370 g. Diabetes bol vyvolaný intravenóznym podaním jednej dávky streptozotocinu (STZ, Sigma, St. Louis, MO) v dávke 45 b mg/kg, ktorý bol rozpustený vo fyziologickom roztoku. Prítomnosť diabetu bola overená nasledujúci deň stanovením glukózy v krvi, akceptované boli hodnoty vyššie ako 15 mmol/1.River Laboratories Inc.), males with an initial weight of 340 to 370 g. Diabetes was induced by intravenous administration of a single dose of streptozotocin (STZ, Sigma, St. Louis, MO) at a dose of 45 b mg / kg, which was dissolved in saline. The presence of diabetes was verified the next day by blood glucose determination, values above 15 mmol / l were accepted.
Testované a kontrolné látky boli podávané zvieratám per os jedenkrát denne.Test and control substances were administered to animals orally once daily.
Zbieranie 24 hodinového moča bolo uskutočnené tak, že zvieratá boli umiestnené jednotlivo do metabolických klietok. Zvieratá príjmali vodu ad libitum, ale neprijmali potravu. Deprivácia potravy bola potrebná aby sa tým predišlo možnej kontaminácii obsahom proteínov v potrave. Moč bol zbieraný do kalibrovaných nádobiek, do ktorých boli pridané kryštály Tymolu (Reanal 3135-1-08-38), aby sa tak zabránilo bakteriálnej kontaminácii.The 24-hour urine was collected by placing the animals individually in metabolic cages. Animals received water ad libitum but did not receive food. Food deprivation was needed to avoid possible protein contamination in the diet. Urine was collected in calibrated containers to which Tymol crystals (Reanal 3135-1-08-38) were added to prevent bacterial contamination.
Pred meraním bol moč centrifugovaný (2 500 rpm) a prefiltrovaný cez filtračný papier (Whatman 1). V prípade potreby boli vzorky moča uskladnené pri -20 °C až kým neboli analyzované.Prior to measurement, urine was centrifuged (2,500 rpm) and filtered through filter paper (Whatman 1). If necessary, urine samples were stored at -20 ° C until analyzed.
Celkový obsah proteínov bol stanovený kolorimetrickou metódou podľa Bradforda (Sigma B-6916, St. Louis, MO) a intenzita zafarbenia bola hodnotená spektrofotometricky (Hitachi-U-3200).Total protein content was determined by the Bradford colorimetric method (Sigma B-6916, St. Louis, MO) and the color intensity was assessed spectrophotometrically (Hitachi-U-3200).
• Výsledky:• The results:
Bimoclomol, podávaný denne v jednej dávke 20 mg/kg, významne znížil stratu proteínov v moči, ktorá bola zvýšená u STZ-diabetických potkanov. Zlúčenina A, podávaná denne v jednej dávke 10 mg/kg, štatisticky nevýznamné znížila stratu proteínov. Avšak (+) enantiomér Zlúčeniny A, podávaný denne v jednej dávke 5 mg/kg významne znížil diabetickú stratu proteínov. Výsledky sú uvedené v Tabuľke 6.Bimoclomol, administered daily as a single dose of 20 mg / kg, significantly reduced protein loss in urine, which was increased in STZ-diabetic rats. Compound A, administered daily as a single dose of 10 mg / kg, did not significantly reduce protein loss. However, the (+) enantiomer of Compound A, administered daily in a single dose of 5 mg / kg, significantly reduced diabetic protein loss. The results are shown in Table 6.
Tabulka 6Table 6
Účinok podávania (+) enantioméru Zlúčeniny A a Bimoclomolu na stratu proteínov močom spôsobenú diabetickou nefropatiou u STZ-diabetických Wistar potkanovEffect of administration of the (+) enantiomer of Compound A and Bimoclomol on urinary protein loss due to diabetic nephropathy in STZ-diabetic Wistar rats
Pokus 6Experiment 6
Účinok 1-mesačného podávania Zlúčeniny A a jej (+) a (-) enantiomérov na patologické zmeny periférnej neuropatie u STZ diabetických Wistar potkanochEffect of 1-month administration of Compound A and its (+) and (-) enantiomers on pathological changes in peripheral neuropathy in STZ diabetic Wistar rats
Materiál a metódy:Material and methods:
Pokusné zvieratá a všetky použité metódy sú rovnaké ako bolo popísané v Pokuse 2.The test animals and all methods used are the same as described in Experiment 2.
Výsledky:The results:
Zlúčenina podávaná denne v jednej dávke 10 mg/kg aCompound administered daily in a single dose of 10 mg / kg a
Zlúčenina A(+) podávaná denne v jednej dávke 5 mg/mg boli ·· rovnako účinné a významne zvýšili motorickú aktivitu (MNCV) a rýchlosť senzorickej vodivosti nervov u diabetických zvierat. Naproti tomu Zlúčenina A(-) nevykazovala významné zlepšenie na žiaden zo sledovaných parametrov. Výsledky sú uvedené v Tabuľke 7.Compound A (+) administered daily as a single 5 mg / mg dose was equally effective and significantly increased motor activity (MNCV) and nerve sensory conductivity in diabetic animals. In contrast, Compound A (-) showed no significant improvement in any of the endpoints. The results are shown in Table 7.
Tabulka 7Table 7
Účinky Zlúčeniny A a jej A(+) a A(-) enantiomérov na zníženú rýchlosť vodivosti nervov (NCV) u STZ diabetických Wistar potkanovEffects of Compound A and its A (+) and A (-) enantiomers on reduced nerve conduction rate (NCV) in STZ diabetic Wistar rats
*** p <0,001 oproti neliečeným STZ-diabetickým zvieratám*** p <0.001 vs untreated STZ-diabetic animals
Pokus 7Attempt 7
Účinky 2-mesačného podávania zlúčeniny A a jej A(+) a A(-) enantiomérov na patologicko histologické zmeny diabetickej retinopatie u STZ diabetických potkanov ··Effects of 2-month administration of Compound A and its A (+) and A (-) enantiomers on pathological histological changes in diabetic retinopathy in STZ diabetic rats
Materiál a metódy:Material and methods:
Pokusné zvieratá a všetky použité metódy sú rovnaké ako bolo popísané v Pokuse 4.The test animals and all methods used are the same as described in Experiment 4.
Výsledky:The results:
Po dvoch mesiacoch podávania A( + ) enantioméru v jednej dennej dávke 5 mg/kg sa významne zlepšili lentikulárne a aj retinálne histologické zmeny spôsobené diabetickou retinopatiou, kým účinok Zlúčeniny A v jednej dennej dávke 10 mg/kg nemal významné účinky a A (-) enantiomér v jednej dennej dávke 5 mg/kg nevykazoval účinok. Čo sa týka histologických zmien na retine, Zlúčenina A a jej A( + ) enantiomér boli účinné a účinok A(-) enantioméru nebol štatisticky významný.After two months of administration of the A (+) enantiomer in a single daily dose of 5 mg / kg, lenticular and also retinal histological changes due to diabetic retinopathy were significantly improved, whereas the effect of Compound A in a single daily dose of 10 mg / kg had significant effects and A (-) the enantiomer at a single daily dose of 5 mg / kg showed no effect. Regarding histological changes on retine, Compound A and its A (+) enantiomer were effective and the effect of the A (-) enantiomer was not statistically significant.
• Výsledky sú uvedené v Tabuľke 8.• The results are shown in Table 8.
Tabuľka 8Table 8
Účinky Zlúčeniny A a jej A(+) a A(-) enantiomérov na histologické zmeny diabetickej retinopatie u STZ diabetických potkanovEffects of Compound A and its A (+) and A (-) enantiomers on histological changes in diabetic retinopathy in STZ diabetic rats
*ρ < 0,05 v porovnaní s neliečenými diabetickými zvieratami **p < 0,01 v porovnaní s neliečenými diabetickými zvieratami* ρ <0.05 compared to untreated diabetic animals ** p <0.01 compared to untreated diabetic animals
Pokus 8Attempt 8
Účinky A(+) a A(-) enantiomérov na in vivo vychytávanie glukózy stimulované inzulínom u zvierat s inzulínovou rezistenciou vyvolanou u zvierat diétouEffects of the A (+) and A (-) enantiomers on insulin-stimulated in vivo glucose uptake in animals with dietary insulin-induced resistance in animals
Materiál a metódy:Material and methods:
V pokusoch boli použité potkany kmeňa Wistar (Charles River Inc.), samce, s počiatočnou hmotnosťou 300 až 350 g.Wistar rats (Charles River Inc.), male, weighing 300-350 g, were used in the experiments.
Inzulínová rezistencia bola navodená zmenou diétneho režimu: zvieratá príjmali vysokotukovú diétu (HF) v priebehu 3 týždňov. Vo vysokotukovej diéte prevládali nasýtené tuky a predstavovali 70 % celkového denného kalorického príjmu. A( + ) a A(-) enantioméry boli podávané denne v dávke 20 mg/kg/deň.Insulin resistance was induced by a change in diet regimen: animals received a high-fat diet (HF) over 3 weeks. Saturated fats predominated in the high-fat diet and accounted for 70% of total daily caloric intake. The A (+) and A (-) enantiomers were administered daily at 20 mg / kg / day.
Na konci troch týždňov podávania boli vyhodnotené nasledujúce parametre: 1. hodnoty cukrov a lipidov v sére a 2. in vivo inzulin-stimulované vychytávanie glukózy metódou euglykemického glukózového zámku, ktorá je bežne považovaná za najpresnejšiu metódu pre kvantitatívne hodnotenie vychytávania glukózy (DeFronzo a spol., Američan Journal of Physiology, 1979/237/E214-233). V krátkosti: koncentrácia glukózy na lačno u zvierat z rôznych skupín musí byť rovnaká. Pokusy boli realizované na bdelých zvieratách s voľným pohybom a s chronickou kanylou: najprv bola zahájená infúzia inzulínu (6,4 mU/kg/min), po ktorej nasledovala a kontinuálna infúzia glukózy tak, aby sa zachovali koncentrácie glukózy v krvi v euglykemických hodnotách. Po stabilizácii bolo hodnotené množstvo infundovanej glukózy v priebehu 90 minút (rýchlosť glukózovej infúzie = GIR, mg/kg/min), čo je kvantitatívnym vyjadrením citlivosti na inzulín.At the end of three weeks of administration, the following parameters were evaluated: 1. serum sugar and lipid values; and 2. in vivo insulin-stimulated glucose uptake by the euglycemic glucose lock method, which is commonly considered to be the most accurate method for quantitatively evaluating glucose uptake (DeFronzo et al. , American Journal of Physiology, 1979/237 / E214-233). In short: the fasting glucose concentration in animals from different groups must be the same. The experiments were carried out on waking animals with free movement and a chronic cannula: insulin infusion (6.4 mU / kg / min) was first initiated, followed by continuous glucose infusion to maintain blood glucose concentrations at euglycemic levels. After stabilization, the amount of infused glucose was assessed over 90 minutes (glucose infusion rate = GIR, mg / kg / min), which is a quantitative indication of insulin sensitivity.
·· ·· ·*·· ·· · *
Výsledky:The results:
A(+) a A(-) enantioméry podávané v jednej dennej dávke 20 mg/kg/min neovplyvnili telesnú hmotnosť a príjem potravy a hladiny krvnej glukózy na lacno.The A (+) and A (-) enantiomers administered at a single daily dose of 20 mg / kg / min did not affect body weight and food intake and blood glucose levels cheaply.
Naproti tomu obe zlúčeniny normalizovali zvýšené hladiny inzulínu a koncentráciu triglyceridov vyvolané príjmom vysokotukovej diéty a rovnako významne znížili obsah triglyceridov vo svaloch. Skúška pomocou euglykemického glukózového zámku ukázala, že vysokotuková diéta významne znížila inzu‘ línom stimulované vychytávanie glukózy: kontroly: 26,7 ± 0,68 mg/kg/min, HF diéta: 15,0 ± 0,39 mg/kg/min.In contrast, both compounds normalized elevated insulin levels and triglyceride concentration induced by intake of a high-fat diet, and also significantly reduced triglyceride content in muscles. The euglycemic glucose lock test showed that a high-fat diet significantly reduced insulin-stimulated glucose uptake: controls: 26.7 ± 0.68 mg / kg / min, HF diet: 15.0 ± 0.39 mg / kg / min.
Takéto zníženie inzulínom stimulovaného vychytávania glukózy je zvýšené podávaním oboch enantiomérov: HF+A(+): 20,5±0,89 mg/kg/min a HF+A(-): 19,7 ±1,38 mg/kg/min (významné zvýšenie v oboch prípadoch je na úrovni p < 0,01).Such a decrease in insulin-stimulated glucose uptake is increased by administration of both enantiomers: HF + A (+): 20.5 ± 0.89 mg / kg / min and HF + A (-): 19.7 ± 1.38 mg / kg / min (significant increase in both cases is p <0.01).
Podía týchto výsledkov oba enantioméry zvýšili vychytávanie glukózy stimulované inzulínom, čím zlepšili inzulínovú rezistenciu.According to these results, both enantiomers increased insulin-stimulated glucose uptake, thereby improving insulin resistance.
Pokus 9 * Antidiabetická aktivita chronického podávania A(+) enantioméru u Zucker Diabetic Fatty potkanovExperiment 9 * Antidiabetic activity of chronic administration of the A (+) enantiomer in Zucker Diabetic Fatty rats
Materiál a metódy:Material and methods:
Zvolil sa genetický model diabetu zvierat a v pokusoch boli použité Zucker Diabetic Fatty (ZDF) potkany. Tento model je diabetickým modelom inzulínovej rezistencie obéznych, nediabetických Zucker fa/fa zvierat (pozri Pokus 1) . U ZDF potkanoch sa vyvinul diabetes vo veku 6 až 8 týždňov, ktorému predchádzala prítomnosť inzulínovej rezistencie.A genetic model of animal diabetes was selected and rats were used in the experiments Zucker Diabetic Fatty (ZDF). This model is a diabetic model of insulin resistance of obese, non-diabetic Zucker fa / fa animals (see Experiment 1). ZDF rats developed 6 to 8 weeks of diabetes, preceded by the presence of insulin resistance.
Hodnotil sa účinok A(+) enantioméru po podávaní množstva 2 x 20 mg/kg/deň počínajúc v nediabetickej fáze a vo veku 7 týždňov; podávanie pokračovalo nasledujúcich 6 týždňov.The effect of the A (+) enantiomer after administration of 2 x 20 mg / kg / day starting in the non-diabetic phase and at 7 weeks of age was evaluated; administration continued for the next 6 weeks.
Klinické parametre boli stanovené štandardnými metódami. Koncentrácie inzulínu v sére boli merané nedávno vyvinutou metódou (ELISA, DRG International, Inc., USA).Clinical parameters were determined by standard methods. Serum insulin concentrations were measured by a recently developed method (ELISA, DRG International, Inc., USA).
Výsledky:The results:
V týchto pokusoch sa získal nový výsledok, že A(+) anantiomér má silnú antidiabetickú aktivitu u diabetických zvierat.In these experiments, a new result was obtained that the A (+) anantiomer has potent antidiabetic activity in diabetic animals.
Výsledky dosiahnuté po 3 a 5 mesiacoch podávania sú . uvedené v Tabuľke 9.The results obtained after 3 and 5 months of administration are. listed in Table 9.
Tabuľka 9Table 9
Koncentrácie glukózy v sére (mmol/1), nasýtený stavSerum glucose concentrations (mmol / l), saturation
*p < 0,02, **p < 0,005 porovnanie voči neliečeným ZDF zvieratám* p <0.02, ** p <0.005 comparison to untreated ZDF animals
Hoci podávanie A(+) enantioméru neupravovalo koncentráciu glukózy v krvi, kombinované účinky silnej antidiabetickej • · aktivity a už v minulosti známej liečivej účinnosti na komplikácie chronického diabetu, dávajú tejto zlúčenine výnimočné vlastnosti.Although administration of the A (+) enantiomer did not regulate blood glucose concentration, the combined effects of potent antidiabetic activity and previously known therapeutic efficacy on complications of chronic diabetes, give this compound exceptional properties.
Na základe nového kombinovaného účinku môže byť významne rozšírená terapeutická indikačná skupina pre používanie A (+) enantioméru.Based on the new combined effect, the therapeutic indication group for the use of the A (+) enantiomer may be significantly extended.
Ďalšie pokusy viedli k záveru, že zlúčeniny podlá vynálezu, okrem ich účinkov na patologické komplikácie diabetu, sú vhodné pre liečenie poškodených periférnych nervov spôsobené diabetom. Tento záver je podporovaný výsledkami v nasledujúcom pokuse zameranom na regeneráciu nervov.Further experiments have led to the conclusion that the compounds of the invention, in addition to their effects on the pathological complications of diabetes, are useful for the treatment of damaged peripheral nerves caused by diabetes. This conclusion is supported by the results of the following experiment aimed at nerve regeneration.
Pokus 10Attempt 10
Terapeutický účinok Zlúčeniny A a jej A(+) enantioméru na regeneráciu nervov u STZ-diabetických Wistar potkanovTherapeutic effect of Compound A and its A (+) enantiomer on nerve regeneration in STZ-diabetic Wistar rats
Materiál a metódy:Material and methods:
V pokusoch sa použili Wistar potkany telesnej hmotnosti 320 až 350 g. Diabetes bol indukovaný a skontrolovaný tak, ako je popísané v Príklade 2. U pokusných diabetických zvierat (diabetes trval 3 týždne) bol poškodený lavý ischiadický nerv mrazením, nerv na pravej strane bol použitý ako nepoškodená kontrola. Pozorovaná regenerácia sa hodnotila zaznamenávaním signálov flexor reflexov vyvolaných dráždením predného tibiálneho nervu, a ktorá bola vyjadrená plochou pod krivkou (AUC) elektromyogramu. Pre stimuláciu a hodnotenie bol použitý systém popísaný v Pokuse 2.Wistar rats weighing 320-350 g were used in the experiments. Diabetes was induced and checked as described in Example 2. In experimental diabetic animals (diabetes lasted 3 weeks) the left sciatic nerve was damaged by freezing, the right side nerve was used as an undamaged control. The observed regeneration was evaluated by recording flexor reflex signals induced by anterior tibial nerve irritation and which was expressed by the area under the curve (AUC) of the electromyogram. The system described in Experiment 2 was used for stimulation and evaluation.
Jedna dávka denne 10 mg/kg Zlúčeniny A a 5 mg/kg A(+) enantioméru bola podávaná počas 5 týždňov po poranení mrazením.A single daily dose of 10 mg / kg of Compound A and 5 mg / kg of the A (+) enantiomer was administered for 5 weeks after freezing injury.
Výsledky:The results:
Na konci 3-týždne trvajúceho diabetu, pred poranením mrazom, sa vyvinula senzorická neuropatia a spôsobila 23 až 25 % pokles AUC na oboch nohách. Po 2 týždňoch od poranenia mrazom sa nepozorovala žiadna odpoveď. V piatom týždni bola prítomná neuroregenerácia v rozsahu 63 %. Regenerácia bola zvýšená na 73 % podávaním Zlúčeniny A, A(+) enantiomér mal účinnosť až 93 %. Ako výsledok podávania A(+) enantioméru sa pozorovala 83 % neuroregeneráci a len 44 % regenerácia nervov po podávaní Zlúčeniny A u zvierat nepoškodených mrazením. Znamená to, že A(+) enantiomér má silný neuroprotektívny účinok.Sensory neuropathy developed at the end of 3 weeks of diabetes, before frost injury, causing a 23-25% decrease in AUC on both legs. No response was observed after 2 weeks of frost injury. At week 5, neuroregeneration was present in the range of 63%. Regeneration was increased to 73% by administration of Compound A, the A (+) enantiomer had an efficacy of up to 93%. As a result of administration of the A (+) enantiomer, 83% of neuroregeneration and only 44% of nerve regeneration were observed after administration of Compound A in animals not damaged by freezing. This means that the A (+) enantiomer has a potent neuroprotective effect.
N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridín-l-oxid3-karboximidoyl chlorid môže byť pripravený nasledovným postupom, ktorý dosiaľ nie je známy.N- [2-hydroxy-3- (1-piperidinyl) -propoxy] -pyridine-1-oxide-3-carboximidoyl chloride can be prepared by the following procedure, which is not yet known.
Podľa oxidačného postupu popísaného v WO 97/16349, derivát oxidovaný na atóme dusíka v oboch kruhoch, alebo tiež menším množstvom reagentu, derivát oxidovaný na alicyklickom kruhu môže byť pripravený z chloridu 0-(3-piperidino-2hydroxy-l-propyl)-3-pyridín hydroxymovej kyseliny, keďže atóm alicyklického dusíka je prednostne oxidovaný. Výber miesta oxidácie má byť taký, aby bol nasmerovaný na pyridínový kruh pre tvorbu zlúčeniny podľa vynálezu, preto bol postup modifikovaný. Hlavným bodom modifikácie je uľahčenie selektívnej oxidácie pyridínového kruhu Oxidácia peroctovej kyseliny sa uskutoční v prítomnosti silnej kyseliny, výhodne metansulfónovej kyseliny, ktorá protonuje alicyklický dusík a tým zabraňuje jeho oxidácii; preto sa stáva oxidácia pyridinu primárnou. Ako oxidačné činidlo môže byť použitá akákoľvek perkyselina, výhodne kyselina peroctová.According to the oxidation procedure described in WO 97/16349, a derivative oxidized on a nitrogen atom in both rings, or also by a smaller amount of reagent, a derivative oxidized on an alicyclic ring can be prepared from O- (3-piperidino-2-hydroxy-1-propyl) -3 chloride -hydroxy-pyridine, since the alicyclic nitrogen atom is preferably oxidized. The selection of the oxidation site should be such that it is directed to the pyridine ring to form the compound of the invention, therefore the procedure has been modified. The main point of modification is to facilitate the selective oxidation of the pyridine ring The oxidation of peracetic acid is carried out in the presence of a strong acid, preferably methanesulfonic acid, which protonates the alicyclic nitrogen and thereby prevents its oxidation; therefore, oxidation of pyridine becomes primary. Any peracid, preferably peracetic acid, can be used as the oxidizing agent.
Opticky aktívne enantioméry zlúčeniny podľa vynálezu sa pripravia použitím vhodného opticky aktívneho enantioméru ·· ·· ·· • · · · · · • ·· · · • · · · · · • · · · · ···· ·· ·· ·· ··The optically active enantiomers of a compound of the invention are prepared using a suitable optically active enantiomer. · ··
chloridu 0-(3-piperidino-2-hydroxy-l-propyl)-3-pyridín hydroximovej kyseliny ako východzieho materiálu, ktorý môže byť pripravený, napríklad, podía EP 0 417 210 BI, rozpustením racemickej zlúčeniny. V priebehu reakcie nie je poškodená chirálna vlastnosť a výsledný výrobok má rovnakú optickú čistotu ako východzia látka.O- (3-piperidino-2-hydroxy-1-propyl) -3-pyridine hydroximic acid chloride as a starting material, which can be prepared, for example, according to EP 0 417 210 B1 by dissolving the racemic compound. The chiral property is not damaged during the reaction and the resulting product has the same optical purity as the starting material.
Keď je potrebné, získaný chlorid N-[2-hydroxy-3-(1piperidinyl)-propoxy]-pyridín-l-oxid-3-karboximidoylu, alebo jeden z jeho opticky aktívnych enatiomérov, môžu byť známymi spôsobmi premenené na adičnú kyslú sol pomocou minerálnej alebo organickej kyseliny.If desired, the resulting N- [2-hydroxy-3- (1-piperidinyl) -propoxy] -pyridine-1-oxide-3-carboximidoyl chloride, or one of its optically active enantiomers, can be converted into the acid addition salt by known methods. mineral or organic acid.
N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridin-l-oxid3-karboximidoyl chlorid, jeho opticky aktívny (+) alebo (-) enantiomér, zmes enantiomérov v akomkoľvek pomere, a racemická zlúčenina, ďalej adičné soli kyseliny vytvorené s ktoroukolvek vyššie uvedenou zlúčeninou s minerálnou alebo organickou kyselinou, predstavujú predmet predkladaného vynálezu. Predmetom vynálezu sú všetky možné geometrické izomérne formy chloridu N-[2-hydroxy-3-(1-piperidinyl)-propoxy]‘ pyridín-l-oxid-3-karboximidoylu. Výraz „stereoizoméry chloridu N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridín-l-oxid3-karboximidoylu sa týkajú všetkých možných optických a geometrických izomérov zlúčeniny.N- [2-hydroxy-3- (1-piperidinyl) -propoxy] -pyridine-1-oxide-3-carboximidoyl chloride, its optically active (+) or (-) enantiomer, a mixture of enantiomers in any ratio, and a racemic compound; acid addition salts formed with any of the aforementioned mineral or organic acid compounds are an object of the present invention. The present invention relates to all possible geometric isomeric forms of N- [2-hydroxy-3- (1-piperidinyl) -propoxy] -pyridine-1-oxide-3-carboximidoyl chloride. The term "stereoisomers of N- [2-hydroxy-3- (1-piperidinyl) -propoxy] -pyridine-1-oxide-3-carboximidoyl chloride" refers to all possible optical and geometric isomers of the compound.
Podía vynálezu sa tieto zlúčeniny používajú pre liečenie patologickej inzulínovej rezistencie a pre liečenie a prevenciu patologických stavov spojených s inzulínovou rezistenciou.According to the invention, these compounds are used for the treatment of pathological insulin resistance and for the treatment and prevention of pathological conditions associated with insulin resistance.
Výhoda uskutočnenia predkladaného vynálezu je v tom, že zlúčeniny sa používajú pre simultánne liečenie alebo prevenciu chronickým diabetom navodených komplikácií, predovšetkým neuropatie a nefropatie, a patologickej inzulínovej rezistencie a tiež patologických stavov spojených s inzulínovou rezistenciou.An advantage of an embodiment of the present invention is that the compounds are used for the simultaneous treatment or prevention of chronic diabetic-induced complications, in particular neuropathy and nephropathy, and pathological insulin resistance, as well as pathological conditions associated with insulin resistance.
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Podlá výhodného uskutočnenia vynálezu chlorid N—[2—— hydroxy-3-(1-piperidinyl)-propoxy]-pyridín-l-oxid-3-karboximidoylu, alebo jeho stereoizoméry alebo adičné soli kyselín sa používajú pre liečenie patologickej inzulínovej rezistencie a s ňou spojených patologických stavov, súčasne sa zvyšuje diabetom indukovaný patologický pokles periférnej neuroregenerácie.According to a preferred embodiment of the invention, N- [2-hydroxy-3- (1-piperidinyl) -propoxy] -pyridine-1-oxide-3-carboximidoyl chloride, or stereoisomers or acid addition salts thereof, are used for the treatment of and with pathological insulin resistance. At the same time, the diabetic-induced pathological decrease in peripheral neuroregeneration is increased.
Zlúčeniny podlá vynálezu môžu byť použité pre liečenie ľudí aj zvierat.The compounds of the invention can be used to treat both humans and animals.
Predmet vynálezu preto zahrňuje spôsob liečenia patologickej inzulínovej rezistencie, liečenie a prevenciu patolo• gických stavov spojených s inzulínovou rezistenciou, keď je pacientom podávaný chlorid N-[2-hydroxy-3-(1-piperidinyl)propoxy]-pyridín-l-oxid-3-karboximidoylu, alebo jeden z jeho stereoizomérov vo forme zásady alebo adičnej soli kyseliny. Výhodné uskutočnenie postupu podlá vynálezu je, keď chlorid N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridin-l-oxid-3-karboximidoylu alebo jeden z jeho streoizomérov, alebo jeho adičnej sú tiež soli s kyselinou, je podávaný pacientovi s diabetickou retinopatiou, neuropatiou alebo nefropatiou.The present invention therefore encompasses a method of treating pathological insulin resistance, treating and preventing pathological conditions associated with insulin resistance when administering N- [2-hydroxy-3- (1-piperidinyl) propoxy] -pyridine-1-oxide- chloride to patients. 3-carboximidoyl, or one of its stereoisomers in base or acid addition salt form. A preferred embodiment of the process according to the invention is that N- [2-hydroxy-3- (1-piperidinyl) -propoxy] -pyridine-1-oxide-3-carboximidoyl chloride or one of its stereoisomers or its addition salts are also acid salts is administered to a patient with diabetic retinopathy, neuropathy or nephropathy.
Podlá iného špecifického uskutočnenia vynálezu je chlorid N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridin-l-ozid-3k karboximidoylu, alebo jeden z jeho stereoizomérov, alebo jeho adičná sol kyseliny, podávaná pacientovi v prípade patologického poklesu neuroregenerácie spôsobenej diabetom.According to another specific embodiment of the invention, N- [2-hydroxy-3- (1-piperidinyl) -propoxy] -pyridine-1-ozide-3 to carboximidoyl, or one of its stereoisomers, or an acid addition salt thereof, is administered to a patient in in the case of a pathological decrease in neuroregeneration caused by diabetes.
Dávka zlúčenín závisí na stave a chorobe pacienta, denná dávka je 0,1 až 400 mg/kg, výhodne 0,1 až 100 mg/kg. V ľudskej terapii, je orálna dávka výhodne 10 až 300 mg, v prípade rektálneho podávania 1 až 15 mg, kým pri parenterálnom podaní je to dávka 1 až 15 mg pre dospelého pacienta.The dose of the compounds depends on the condition and the disease of the patient, the daily dose being 0.1 to 400 mg / kg, preferably 0.1 to 100 mg / kg. In human therapy, the oral dose is preferably 10 to 300 mg, for rectal administration 1 to 15 mg, while for parenteral administration, it is 1 to 15 mg for an adult patient.
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Tieto dávky sú výhodne podávané vo forme jednej dávky, ktorá môže byť v niektorých prípadoch rozdelená do 2 až 3 menších dávok cez deň, predovšetkým pri podávaní per os.These doses are preferably administered in the form of a single dose, which may, in some cases, be divided into 2 to 3 smaller doses per day, particularly when administered orally.
Výhodne sa používa stereoizomér racemickej zlúčeniny, najvýhodnejšie (+) enantiomér. V tomto prípade je pre liečenie dostatočné menšie množstvo aktívnej zložky.Preferably, the stereoisomer of the racemic compound is used, most preferably the (+) enantiomer. In this case, a smaller amount of the active ingredient is sufficient for treatment.
Predmetom vynálezu sú tiež farmaceutické prípravky vhodné pre liečenie. Tieto farmaceutické kompozície, okrem bežných doplnkových látok a nosičov obsahujú ako aktívnu zložku obsahujú chlorid N-[2-hydroxy-3-(1-piperidinyl)-propoxy]pyridín-l-oxid-3-karboximidoylu alebo jeden z jeho stereoizomérov, alebo niektorú jeho adičnú soľ kyseliny.The present invention also provides pharmaceutical compositions suitable for treatment. These pharmaceutical compositions, in addition to conventional additives and carriers, contain N- [2-hydroxy-3- (1-piperidinyl) -propoxy] pyridine-1-oxide-3-carboximidoyl chloride or one of its stereoisomers as an active ingredient or an an acid addition salt thereof.
Farmaceutické kompozície podľa vynálezu môžu byť pripravené vo forme pevných alebo kvapalných prípravkov používaných pri liečení ľudí a zvierat. Môžu byť pripravené potiahnuté tablety, granuly, kapsule, roztoky alebo sirupy, čipky pre rektálne podávanie, a pre parenterálne podanie lyofilizované alebo nelyofilizované injekcie alebo infúzne roztoky, ktoré môžu byť pripravené bežnými spôsobmi. Výrobky pre perorálne používanie môžu obsahovať plnivá ako mikrokryštalická celulóza, škrob alebo laktóza; mazivá, ako kyselina steárová alebo stearát horečnatý; pokrývači materiál, ako cukor; film vytvárajúci materiál, ako hydroxymetylcelulóza; sladidlá a vonné látky, ako metylparabén alebo sacharín, alebo farbiace látky. Čipky môžu obsahovať kakaové maslo alebo polyetylénglykol. Parenterálne výrobky môžu obsahovať, okrem účinnej látky, soľný roztok, alebo v niektorých prípadoch dispergačné látky, ako je propylénglykol.The pharmaceutical compositions of the invention may be prepared in the form of solid or liquid preparations used in the treatment of humans and animals. Coated tablets, granules, capsules, solutions or syrups, suppositories for rectal administration, and for parenteral administration, lyophilized or non-lyophilized injections or infusion solutions may be prepared, which may be prepared by conventional methods. Products for oral use may contain fillers such as microcrystalline cellulose, starch or lactose; lubricants such as stearic acid or magnesium stearate; a coating material such as sugar; a film-forming material such as hydroxymethylcellulose; sweeteners and fragrances, such as methyl paraben or saccharin, or coloring agents. The suppositories may contain cocoa butter or polyethylene glycol. Parenteral products may contain, in addition to the active ingredient, a saline solution or, in some cases, dispersants such as propylene glycol.
Vynález je ďalej znázornený nasledovnými príkladmi.The invention is further illustrated by the following examples.
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Príklady uskutočnenia vynálezuDETAILED DESCRIPTION OF THE INVENTION
Príklad 1Example 1
Príprava chlorid N-[2-hydroxy-3-(1-piperidinyl)-propoxy]pyridín-l-oxid-3-karboximidoylu (Z)-2-butendioat (1:1)Preparation of N- [2-hydroxy-3- (1-piperidinyl) -propoxy] pyridine-1-oxide-3-carboximidoyl chloride (Z) -2-butenedioate (1: 1)
40,4 g (0,136 mol) N-[2-hydroxy-3-(1-piperidinyl)propoxy]-pyridin-karboximidoyl chloridu bolo rozpustených v zmesi 238 ml ladovej kyseliny octovej a 13,0 g (0,136 mol) kyseliny metansulfónovej. Pridalo sa 61,5 ml (0,591 mol) 30 % peroxidu vodíka pri teplote 60 °C. Reakčná zmes bola miešaná pri teplote 60 °C počas 3,5 až 4 hodín. Roztok bol ochladený na 10 °C a potom bolo pridaných 91 ml roztoku 0,5 M Na2S2O5. Z roztoku bolo oddestilovaných 315 ml zmesi voda-kyselina octová, do ktorej bolo pridaných 250 ml 4 N NaOH, aby pH roztoku bolo 10,55. Potom nasledovalo pretrepávanie s chloroformom. Chloroformová fáza bola premytá vodou, vysušená, pridalo sa čierne uhlie a chloroform bol odparený. K zvyšku bola pridaná voda, roztok bol extrahovaný izopropyl éterom a potom chloroformom. Chloroformová fáza bola vysušená, pridalo sa čierne uhlie, potom bola prefiltrovaná a odparená. Zvyšok bol rozpustený v acetóne a premenený na soľ pôsobením kyseliny maleinovej. Zrazenina bola prefiltrovaná, premytá40.4 g (0.136 mol) of N- [2-hydroxy-3- (1-piperidinyl) propoxy] -pyridine-carboximidoyl chloride were dissolved in a mixture of 238 ml of glacial acetic acid and 13.0 g (0.136 mol) of methanesulfonic acid. 61.5 ml (0.591 mol) of 30% hydrogen peroxide was added at 60 ° C. The reaction mixture was stirred at 60 ° C for 3.5 to 4 hours. The solution was cooled to 10 ° C and then 91 mL of a 0.5 M Na 2 S 2 O 5 solution was added. 315 ml of a water-acetic acid mixture was distilled from the solution, to which 250 ml of 4 N NaOH was added to bring the pH of the solution to 10.55. This was followed by shaking with chloroform. The chloroform phase was washed with water, dried, charcoal was added and the chloroform was evaporated. Water was added to the residue, the solution was extracted with isopropyl ether and then with chloroform. The chloroform phase was dried, charcoal was added, then filtered and evaporated. The residue was dissolved in acetone and converted to the salt by treatment with maleic acid. The precipitate was filtered, washed
(d, 1H, 4-pyridin) ; 7,55 (m, 1H, 5-pyridín) ; 6,00 (s, 2H,(d, 1H, 4-pyridine); 7.55 (m, 1H, 5-pyridine); 6.00 (s, 2 H,
CH=CH); 4,23-4,48 (m, 3H, CH-OH a NOCH2) ; 2,95-3,50 (m, 6H, 3 x NCH2) ; 1,20-1, 90 (m, 6H, piperidín: 3 x CH2) .CH-CH); 4.23-4.48 (m, 3H, CH-OH and NOCH 2); 2.95-3.50 (m, 6H, 3 x NCH2); 1.20 to 1, 90 (m, 6H, piperidine: 3 x CH2).
·· ·· ·· • ·· · • · · · · ·· ·· • · • · • · · · ···· ·· ·· 13C-NMR (rozpúšťadlo: DMSO; porovnanie: DMSO; v = 300 MHz) [ppm]: 167,6 (2C, 2COOH); 141,0 (2-pyridín); 136,8 (6pyridin); 136,4 (2C, CH=CH); 133,4 (CC1) ; 131,9 (3-pyridín); 127,2 (4-pyridín); 123,6 (5-pyridin); 77,96 (NOCH2) ; 63,6 (CH2N) ; 58,3 (CHOH); 52,0-55, 0 (2C, pyridin: 2 x NCH2) ; 22,6 a 21,7 (3C, pyridin: 3 x CH2) . 13 C-NMR (solvent: DMSO; comparison: DMSO; v = 300 MHz) [ppm]: 167.6 (2C, 2COOH); 141.0 (2-pyridine); 136.8 (6-pyridine); 136.4 (2C, CH-CH); 133.4 (CC1); 131.9 (3-pyridine); 127.2 (4-pyridine); 123.6 (5-pyridine); 77.96 (NOCH 2 ); 63.6 (CH 2 N); 58.3 (CHOH); 52.0-55.0 (2C, pyridine: 2 x NCH 2 ); 22.6 and 21.7 (3C, pyridine: 3 x CH 2 ).
Príklad 2Example 2
Príprava chloridu (+)-/R/-N-[2-hydroxy-3-(1-piperidinyl)propoxy]-pyridín-l-oxid-3-karboximidoylu (Z)-2-butendiolátu (1:1)Preparation of (+) - N - [2-hydroxy-3- (1-piperidinyl) propoxy] -pyridine-1-oxide-3-carboximidoyl (Z) -2-butenediolate chloride (1: 1)
Zopakoval sa postup popísaný v Príklade 1 s tým rozdielom, že namiesto racemického chloridu N-[2-hydroxy-3(1-piperidinyl)-propoxy]-pyridin karboximidoylu bol použitý jeho R enantiomér. Čistá forma bola izolovaná kryštalizáciou z hexánu surovej zásady.The procedure described in Example 1 was repeated except that its R enantiomer was used in place of racemic N- [2-hydroxy-3- (1-piperidinyl) -propoxy] -pyridine carboximidoyl chloride. The pure form was isolated by crystallization from hexane of the crude base.
Výťažok: 31 %Yield: 31%
Bod topenia: 91 až 93 °CMelting point: 91-93 ° C
IR (KBr, cm-1): 3167 (br); 2840; 2710; 1575; 1560; 1480; 1443 (br); 1293 (s); 1279 (s); 1093; 1053; 1043; 1023 (s); 834 (s); 810; 688IR (KBr, cm -1 ): 3167 (br); 2840; 2710; 1575; 1560; 1480; 1443 (br); 1293 (s); 1279 (s); 1093; 1053; 1043 1023 (s); 834 (s); 810; 688
Podlá potreby môže byť tiež pripravená sol maleinanu zo surovej bázy v acetónovom roztoku, ako je popísané v Príklade 1.If desired, a maleate salt of the crude base in acetone solution as described in Example 1 can also be prepared.
Výťažok: 33 %Yield: 33%
Bod topenia: 132,0 až 133,0 °CMelting point: 132.0-133.0 ° C
Pomer enantiomérov: 98/2 (HPLC meranie na Chiral AGP 100 x 4 mm kolóne).Enantiomer ratio: 98/2 (HPLC measurement on a Chiral AGP 100 x 4 mm column).
^-NMR a 13C-NMR: rovnaké ako spektrum racemickej zlúčeniny.1 H-NMR and 13 C-NMR: same as the spectrum of the racemic compound.
··· ·
Príklad 3Example 3
Príprava chloridu (-)-/S/-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridín-l-oxid-3-karboximidoylu (Z)-2-butendioátu (1:1)Preparation of (-) - [S] -N- [2-hydroxy-3- (1-piperidinyl) -propoxy] -pyridine-1-oxide-3-carboximidoyl (Z) -2-butenedioate (1: 1) chloride
Použil sa postup z Príkladu 1 s tým rozdielom, že namiesto racemického chloridu N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-pyridin-karboximidoylu bol použitý S enantiomér.The procedure of Example 1 was followed except that the S enantiomer was used instead of racemic N- [2-hydroxy-3- (1-piperidinyl) propoxy] -3-pyridinecarboximidoyl chloride.
Výťažok: 34 %Yield: 34%
Bod topenia: 132,0 - 133,0 °CMelting point: 132.0-133.0 ° C
Pomer enantiomérov: 98/2 (HPLC meranie na Chiral AGP 100 x 4 mm kolóne).Enantiomer ratio: 98/2 (HPLC measurement on a Chiral AGP 100 x 4 mm column).
1H-NMR a 13C-NMR: rovnaké ako spektrum racemick.ej zlúčeniny. 1 H-NMR and 13 C-NMR: same as the spectrum of the racemic compound.
Príklad 4Example 4
Tableta (+)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridín-l-oxid-3-(+) - N- [2-Hydroxy-3- (1-piperidinyl) -propoxy] -pyridine-1-oxide-3- tablet
Jemne pomletá aktívna zložka bola zmiešaná s doplnkovým materiálom, zmes bola homogenizovaná a granulovaná. Granulát bol potom zlisovaný do tabliet.The finely divided active ingredient was mixed with the additive material, homogenized and granulated. The granulate was then compressed into tablets.
• ·• ·
h*h *
Aktívna zložka bola zmiešaná s doplnkovým materiálom, zmes bola homogenizovaná a naplnená do želatínových toboliek.The active ingredient was mixed with the additive material, homogenized and filled into gelatin capsules.
Príklad 6Example 6
Dražédragee
N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridin-l-oxid-3-Of N- [2-hydroxy-3- (1-piperidinyl) -propoxy] -pyridine-l-oxide-3
Aktivna zložka a polyvinyl pyrolidon boli rozpustené v etanole. Zmes laktózy a zemiakového škrobu boli navlhčené granulačným roztokom aktívnej zložky. Po prefiltrovaní bol granulát vysušený pri 50 °C. Pridal sa stearát horečnatý a zmes bola lisovaná za tvorby tabliet, ktoré boli potom pokryté cukrovou vrstvou a vyleštené pridaním včelieho vosku.The active ingredient and polyvinyl pyrrolidone were dissolved in ethanol. The mixture of lactose and potato starch was moistened with a granulating solution of the active ingredient. After filtration, the granulate was dried at 50 ° C. Magnesium stearate was added and the mixture was compressed to form tablets, which were then coated with a sugar layer and polished by the addition of beeswax.
··· ·
Kakaové maslo a čipková hmota boli zahriate na 40 °C.Cocoa butter and lace mass was heated to 40 ° C.
Aktívna zložka bola dispergovaná v roztopenej zmesi, potom bola zmes naplnená do tvárnic pre čipky.The active ingredient was dispersed in the molten mixture, then the mixture was filled into lace blocks.
Príklad 8Example 8
Roztok (+)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridín-l-oxid-3-karboximidoyl chlorid hydrochlorid sorbitol sacharín sodný redestilovaná voda(+) - N- [2-hydroxy-3- (1-piperidinyl) -propoxy] -pyridine-1-oxide-3-carboximidoyl chloride hydrochloride sorbitol saccharin sodium redistilled water
q.s. adqs ad
Príklad 9Example 9
Injekcie ( + )-N-[2-hydroxy-3-(1-piperidinyl) -propoxy]-pyridín-l-oxid-3-karboximidoyl chlorid maleinan apyrogénny fyziologický roztok, sterilnýInjections of (+) -N- [2-hydroxy-3- (1-piperidinyl) -propoxy] -pyridine-1-oxide-3-carboximidoyl chloride maleic pyrogen-free saline, sterile
500,0 mg500.0 mg
10, 0 g10.0 g
0,05 g0.05 g
100 ml mg100 ml mg
q.s.ad 2,0 mlq.s.ad 2.0 ml
Roztok bol naliaty do dvoch ampuliek a potom boli ampule zatavené.The solution was poured into two vials and then the vials were sealed.
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Príklad 10Example 10
Infúzny roztokSolution for infusion
Bolo pripravených 500 ml infúzneho roztoku s obsahom:500 ml solution for infusion containing:
N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridín-l-oxid-3-karboximidoyl chlorid maleinan 20,0 mg apyrogénny fyziologický roztok, sterilný q.s ad 500 mlN- [2-hydroxy-3- (1-piperidinyl) -propoxy] -pyridine-1-oxide-3-carboximidoyl chloride maleic 20.0 mg pyrogen-free saline, sterile q.s ad 500 ml
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| PCT/HU2000/000015 WO2000050403A1 (en) | 1999-02-26 | 2000-02-24 | N-[2-hydroxy-3-(1-piperidinyl)propoxy]pyridine-1-oxide-3-carboximidoyl chloride and its use in the treatment of insulin resistance |
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| CN1615296A (en) | 2002-01-11 | 2005-05-11 | 拜奥列克斯研究发展公司 | Carboxamidine derivatives and their use in the treatment of vascular diseases |
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| EP3448382B1 (en) | 2016-04-29 | 2020-10-14 | Orphazyme A/S | Arimoclomol for treating glucocerebrosidase associated disorders |
| US20200085812A1 (en) | 2017-05-24 | 2020-03-19 | Orphazyme A/S | Heat shock protein inducers and frontotemporal disorders |
| WO2019229078A1 (en) | 2018-05-28 | 2019-12-05 | Orphazyme A/S | Hsp70 protein levels in pbmc samples as biomarker for disease |
| HUP1800298A1 (en) | 2018-08-30 | 2020-05-28 | N Gene Res Laboratories Inc | Combination of beta blocker and hydroximic acid derivative with reduced side effects |
| WO2021116487A1 (en) | 2019-12-13 | 2021-06-17 | Som Innovation Biotech, S.A. | Compounds for use in the treatment of niemann-pick c disease |
| CA3183559A1 (en) | 2020-06-24 | 2021-12-30 | Thomas Kirkegaard Jensen | Arimoclomol for treating gaucher disease |
| US20230416224A1 (en) * | 2020-11-19 | 2023-12-28 | Zevra Denmark A/S | Processes for preparing arimoclomol citrate and intermediates thereof |
| WO2022136640A1 (en) | 2020-12-24 | 2022-06-30 | Orphazyme A/S | Arimoclomol for the treatment of niemann pick disease, type c, in patients with er type missense mutations |
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| HU207988B (en) * | 1988-10-20 | 1993-07-28 | Biorex Kutato Fejlesztoe Kft | Process for producing halogenides of o-/3-amino-2-hydroxy-propyl/hydroximic acid and pharmaceutical compositions containing them as active components |
| HU222994B1 (en) * | 1995-11-02 | 2004-01-28 | BIOREX Kutató és Fejlesztő Rt. | Hydroxylamine derivatives and use thereof in the preparation of a pharmaceutical compositions for enhancing of molecular chaperon production of cells |
| HUT78138A (en) * | 1995-12-22 | 2000-09-28 | BIOREX Kutató és Fejlesztő Rt | Composition for improvement of cultivation of plants comprising hydroximic acid derivative and use thereof |
| UA64716C2 (en) * | 1996-08-09 | 2004-03-15 | Pharmaceuticals for therapy or prevention of illnesses connected with dysfunction of vascular endothelial cells | |
| HU220971B1 (en) | 1997-04-03 | 2002-07-29 | BIOREX Kutató és Fejlesztő Rt. | Process for producing 0-(3-amino-2-hidroxy-propyl)-hidroxim acid halogenids |
| HUP0001583A2 (en) * | 2000-04-18 | 2002-11-28 | BIOREX Kutató és Fejlesztő Rt. | A pyridine-1-oxide derivative and process for its transformation into pharmaceutically effective compounds |
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| Date | Code | Title | Description |
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| MM4A | Patent lapsed due to non-payment of maintenance fees |
Effective date: 20110224 |